The instant invention relates to novel imidazole and 1,2,4-triazole derivatives which antagonize the binding of angiotensin II (AII) to cellular receptors. This AII antagonist property renders these compounds useful for treatment of angiotensin-related hypertension.
The enzyme renin acts on a blood plasma .alpha..sub.2 -globulin, angiotensinogen, to produce angiotensin I, which is then converted by angiotensin-converting enzyme to AII. The latter substance is a powerful vasopressor agent which has been implicated as a causative agent for producing high blood pressure in various mammals, such as rats, dogs, and humans. The compounds of this invention inhibit the action of AII at its receptors on target cells and thus prevent the increase in blood pressure produced by this hormone-receptor interaction. By administering a compound of the instant invention to a species of mammal with hypertension due to AII, the blood pressure is reduced. The compounds of the invention are also useful for the treatment of congestive heart failure, hyperaldosteronism and glaucoma.
European Application Number 253,310 (U.S. Pat. No. 5,138,069) discloses imidazoles of the formula ##STR1##
The compounds are disclosed as having utility in treating hypertension and congestive heart failure.
European Application Number 323,841 discloses substituted pyrrole-, pyrazole-, and triazole-containing compounds of the formulas ##STR2##
European Application Number 324,37 (U.S. Pat. Nos. 5,128,355 and 5,138,069) discloses a pharmaceutical composition of a diuretic or a nonsteroidal antiinflammatory drug useful for blocking the angiotensin II receptor.
U.S. Pat. No. 4,355,040 discloses imidazole-5-acetic acid derivatives of the formula ##STR3## wherein R.sup.1 is lower alkyl, cycloalkyl or, phenyl which may be substituted with one to three of halogen, nitro, amino, mono(lower alkyl)amino, di(lower alkyl)amino, lower alkyl, lower alkoxyl, benzyloxyl or/and hydroxyl; X.sup.1, X.sup.2, and X.sup.3 are each hydrogen, halogen, nitro, amino, lower alkyl, lower alkoxyl, benzyloxyl or hydroxyl; Y is halogen and R.sup.2 is hydrogen or lower alkyl; provided that X.sup.1 is halogen, lower alkyl, lower alkoxyl, benzyloxyl or hydroxyl when R.sup.1 is unsubstituted or substituted phenyl only with one halogen, di(lower alkyl)amino, lower alkyl or lower alkoxyl, and its salts. The compounds are disclosed as having antihypertensive activity.
European Applications Numbers 403158 and 403159 disclose angiotensin II receptor antagonists of formula ##STR4## wherein R.sup.1 is phenyl, biphenyl, naphthyl, or adamantylmethyl, which are unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C.sub.1 -C.sub.4 -alkyl nitro CO.sub.2 R.sup.7 tetrazol-5-yl C.sub.1 -C.sub.4 -alkoxy, hydroxy, SC.sub.1 -C.sub.4 alkyl, SO.sub.2 NHR.sup.7, SO.sub.3 H, CONR.sup.7 R.sup.7, CN, SO.sub.2 C.sub.1 -C.sub.4 alkyl or C.sub.n F.sub.2n1, wherein n is 1 to3;
R.sup.2 is C.sub.2 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, , or (CH.sub.2).sub.0-3 phenyl unsubstituted or substituted by one to three substituents selected from C.sub.1 -C.sub.4 alkyl, nitro, Cl, Br, F, I, hydroxy, C.sub.1 -C.sub.4 alkoxy, or NR.sup.7 R.sup.7 ; PA1 X is a single bond, S, or O: PA1 R.sup.3 is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, COOR.sup.7, CONR.sup.7 R.sup.7, NO.sub.2, or C.sub.n F.sub.2n1, wherein n is 1 to 3; PA1 R.sup.4 and R.sup.5 are independently hydrogen, C.sub.1 -C.sub.5 alkyl, phenyl--Y--, naphthyl--Y--, or biphenyl--Y--, wherein the aryl groups are unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C.sub.1 -C.sub.4 alkoxy, hydroxy, CO.sub.2 R.sup.7, CN, NO.sub.2, tetrazol-5-yl, SO.sub.3 H, CF.sub.3, CONR.sup.7 R.sup.7, SO.sub.2 NHR.sup.7, C.sub.1 -C.sub.4 -alkyl, or NR.sup.7 R.sup.7, or by methylenedioxy, phenoxy, or phenyl, except that R.sup.4 and R.sup.5 are not both selected from hydrogen or C.sub.1 -C.sub.6 alkyl; PA1 Y is a single bond, O, S, or C.sub.1 -C.sub.6 alkyl which is straight or branched or optionally substituted by phenyl or benzyl, wherein each of the aryl groups is unsubstituted or substituted by halo, NO.sub.2, CF.sub.3, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, CN, or CO.sub.2 R.sup.7 ; PA1 R.sup.6 is --Z--COOR.sup.6 or --Z--CONR.sup.7 R.sup.7 ; PA1 Z is a single bond, vinyl, CH.sub.2 --O--CH.sub.2 --, methylene optionally substituted by C.sub.1 -C.sub.4 alkyl, one or two benzyl groups, thienylmethyl, or furylmethyl, or --C(O)NHCHR.sup.9 --, wherein R.sup.9 is H, C.sub.1 -C.sub.4 alkyl, phenyl, benzyl, thienylmethyl, or furylmethyl; PA1 each R.sup.7 independently is hydrogen, C.sub.1 -C.sub.4 alkyl, or (CH.sub.2).sub.m phenyl, wherein m is 0 to 4; and PA1 R.sup.6 is hydrogen, C.sub.1 -C.sub.6 alkyl, or 2-di(C.sub.1 -C.sub.4 alkyl)amino-2-oxoethyl; or PA1 R.sup.5 and R.sup.6 are both hydrogen, R.sup.4 is and --Z--COOR.sup.8 and Z is other than a single bond; or a pharmaceutically acceptable salt thereof.
Copending U.S. application Ser. No. 07/757021 covers novel anilide derivatives which antagonize the binding of angiotensin II to its receptors. The compounds are those of formula ##STR5##